The Filoviridae family contains multiple highly pathogenic viruses that cause hemorrhagic fever in humans. Outbreaks of Ebola, Sudan, Bundibugyo, and Marburg viruses are unpredictable, can spread rapidly, and occur with 40-90% human lethality. Vaccination efforts for the Zaire ebolavirus (EBOV) show tremendous promise. The candidate vaccines, however, provides no protection against the other filoviruses with equivalent outbreak potential. We and others have recently identified two epitopes on Ebola virus glycoprotein (GP) that elicit antibodies that cross- react with, neutralize, and protect against other all ebolaviruses in animal models. These epitopes are not shared with the much more abundant, secreted soluble GP (sGP), which may serve as an antibody decoy during infection. Here, we propose to use structure-guided design to engineer immunogens that preferentially display these unique GP-specific (i.e. non-sGP), critical, and highly conserved structures and elicit high levels of such broadly-neutralizing and broadly protective antibodies against these epitopes. This three-PI program combines the expertise of (1) a pioneer in the field of structure-based and epitope-focused vaccine design, (2) the structural biologist who has determined most filovirus GP-antibody structures and handles the majority of the world?s filovirus antibodies, and (3) a leading expert in filovirus vaccines and immunology. In this highly collaborative program, iterative stages of innovative design and functional evaluation will lead to novel immunogens that could be used alone or in a prime-boost regimen with single-virus vaccines currently in clinical trials. Milestones along the way demonstrate progress in provision of novel structures, design of stable and immunogenic features, and elicitation of broadly-reactive and broadly- protective immune responses against the array of filovirus threats. The proposed program is designed to deliver a vaccine with demonstrated efficacy against Zaire ebolavirus, Sudan ebolavirus, and Bundibugyo ebolavirus infections in guinea pig and ferret models as well as efficacy in NHP models of Sudan and Ebola virus infections.